Abstract The objectives of this proposal are to characterize the pathological roles of AEP-cleaved APP and AEP-cleaved Tau fragments in Alzheimer's disease (AD) onset and progression and how AEP is molecularly regulated during ageing. AEP is an acidosis-activated protease with a high level of specificity for cleavage of protein substrates after an asparagine residue. AD is characterized by the accumulation of the ?-amyloid peptide (A?) within the brain along with hyperphosphorylated and cleaved forms of the microtubule-associated protein Tau. Endogenous AEP is inhibited by Cystatin E/M, an A?-associated protein, preventing neurodegeneration in AD. Most recently, we show that AEP is activated by A? and cleaves APP and Tau in human AD brains and mediates AD pathology. Notably, AEP is expressed in brain and spinal cord in an age-dependent manner. We found that AEP upregulation and activation tightly correlate with APP and Tau fragmentation during ageing. Strikingly, we found that C/EBP?, an age-dependent transcription factor, plays a critical role in regulating AEP expression during ageing. Hence, we hypothesize that AEP may play a critical role in mediating AD pathogenesis, which is mediated by C/EBP?. Successful completion of the proposed studies will lead to the identification of a novel drug target for treatment of neurodegenerative diseases including AD.